Neurotrophic factors, or neurotrophins, are agents that can prevent neuronal death (neurotrophism) or promote axonal growth (neurotropism). To date, all widely studied neurotrophins (c.f. NGF, BDNF, GDNF, NT4/5, NT6) are naturally occurring polypeptides or proteins (Bennett, et al., Auton. Neurosci. 2002, 95, 1; Lu, et al., J. Comp. Neurol. 2001, 436, 456; Kaneko, J. Med. Chem. 1997, 40, 1863). Given their potential to treat neurodegenerative disorders, it is not surprising that neurotrophic factors have been the focus of considerable interdisciplinary research since the discovery of the first neurotrophin, NGF, by Montalcini and Hamburger (Levi-Montalcini, et al., J. Exp. Zool. 1951, 116, 321-362). Indeed, peptidyl neurotrophic factors have been extensively evaluated in animal models for their ability to treat neurodegenerative disease. However, due to unfavorable drug delivery and pharmacokinetic characteristics, in vivo evaluation of these neurotrophins requires direct microinjection into the brain (Kaneko, J. Med. Chem. 1997, 40, 1863; Kirik, et al., Nature Neuroscience 2004, 7, 105; Dawbarn, et al., Neuropathology and Applied Neurobiology 2003, 29, 211-30; Pollack, et al., Curr. Drug Target CNS Neurol. Disord. 2002, 1, 59; Gonzalez, et al., Brain Res. 2001, 920, 65; Fournier, J. Pharm. Pharmacol. 1998, 50, 323). Clearly, drug availability problems associated with these polypeptidic structures are a serious impediment to their development in prospective human settings.
In 1995, Fukayama, Shida, and Kodama reported the isolation and structural characterization of the neurotrophically inactive sesquiterpenoid tashironin (2) from the wood of illicium tashiroi (Fukuyama, et al., Tetrahedron Lett. 1995, 36, 583). More recently, Fukuyama and coworkers reported on the isolation and structure elucidation of 11-O-debenzoyltashironin (1), which promotes neurite growth at concentrations as low as 0.1 μmol. (Huang, et al., J. Nat. Prod. 2001, 64, 428).